The Mycobacterial Cell Envelope: A Relict From the Past or the Result of Recent Evolution?

Abstract

Mycobacteria are well known for their taxonomic diversity, their impact on global health, and for their atypical cell wall and envelope. In addition to a cytoplasmic membrane and a peptidoglycan layer, the cell envelope of members of the order Corynebacteriales, which include Mycobacterium tuberculosis, also have an arabinogalactan layer connecting the peptidoglycan to an outer membrane, the so-called “mycomembrane.” This unusual cell envelope composition of mycobacteria is of prime importance for several physiological processes such as protection from external stresses and for virulence. Although there have been recent breakthroughs in the elucidation of the composition and organization of this cell envelope, its evolutionary origin remains a mystery. In this perspectives article, the characteristics of the cell envelope of mycobacteria with respect to other actinobacteria will be dissected through a molecular evolution framework in order to provide a panoramic view of the evolutionary pathways that appear to be at the origin of this unique cell envelope. In combination with a robust molecular phylogeny, we have assembled a gene matrix based on the presence or absence of key determinants of cell envelope biogenesis in the Actinobacteria phylum. We present several evolutionary scenarios regarding the origin of the mycomembrane. In light of the data presented here, we also propose a novel alternative hypothesis whereby the stepwise acquisition of core enzymatic functions may have allowed the sequential remodeling of the external cell membrane during the evolution of Actinobacteria and has led to the unique mycomembrane of slow-growing mycobacteria as we know it today.

One or two membranes? Diderm Firmicutes challenge the Gram‐positive/Gram‐negative divide

“…It is worth noting that within the classical monoderm Actinobacteria, the cell envelope of Corynebacteriales (which include Mycobacteria) contains mycolic acid and forms a barrier on the outer surface of cells. However, this structure is not homologous to the classical diderm OM and likely arose independently (Vincent et al, ). Accordingly, no OM markers are found in this clade.…”

Host Cell Targets of Released Lipid and Secreted Protein Effectors of Mycobacterium tuberculosis

“…Another group is composed of the lipid DIM/PDIM and its glycosylated form the phenol glycolipids (PGLs). PDIM are only produced by pathogenic mycobacteria in the MTB complex (Goren et al, 1974;Vincent et al, 2018). PDIM-deficient strains are attenuated in the Guinea pig model (Goren et al, 1974), and these findings could be confirmed, two decades later, after a screening of a transposon mutant library of H37Rv for loss of in vivo virulence in the mouse model (Camacho et al, 1999;Cox et al, 1999).…”

“…Mtb produces a wide variety of unique lipids which are important for host cell manipulation and virulence of Mtb (Neyrolles and Guilhot, 2011;Arbues et al, 2014;Gago et al, 2017;Queiroz and Riley, 2017). These lipids are localized in the mycobacterial envelope and have a very unique structure and role for pathogenesis (reviewed in Vincent et al, 2018;Dulberger et al, 2020, Figure 3). Briefly, the envelope consists of: (1) a plasma membrane which is mainly composed of phospholipids, (2) a superstructure made up of a layer of peptidoglycan covalently linked to arabinogalactan, and (3) a mycomembrane which as its inner leaflet has mycolic acids that are esterified with the underlying arabinogalactan (Figure 3).…”

“…Briefly, the envelope consists of: (1) a plasma membrane which is mainly composed of phospholipids, (2) a superstructure made up of a layer of peptidoglycan covalently linked to arabinogalactan, and (3) a mycomembrane which as its inner leaflet has mycolic acids that are esterified with the underlying arabinogalactan (Figure 3). The outer leaflet of the mycomembrane is made up of a wide variety of lipids and almost all of them are involved in the host immune response manipulation by Mtb (Vincent et al, 2018;Daffe and Marrakchi, 2019;Dulberger et al, 2020) (Figure 3).…”

Aggregation of nontuberculous mycobacteria is regulated by carbon:nitrogen balance

“…Regardless of the signal transduction mechanism, a surface adhesin must mediate the aggregation phenotype. Like many members of the Corynebacteriales order, mycobacteria produce a mycomembrane: a cell wall composed of peptidoglycan, arabinogalactan covalently linked to an inner leaflet of long-chain mycolic acids, and an outer layer of extractable lipids, lipoglycans, and proteins (56, 57). As such, the mycobacterial cell wall is unusually lipid rich (58, 59).…”